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  • The production of antibodies is a key immune response to viruses, bacteria or other pathogens, but it’s not the body’s only way of fighting infection.
  • Booster doses are seen as a way to shore up the immune protection against SARS-CoV-2, the coronavirus that causes COVID-19.
  • But some experts are questioning whether booster shots will be needed or if our immune systems are robust enough to not need additional vaccine doses.

As some countries roll out booster doses of COVID-19 vaccines, conversations over whether these additional doses are needed right now have centered on three things — breakthrough infections, waning antibody levels, and the Delta variant.

All of these, of course, are interrelated.

The concern is that as antibody levels decline during the months after full vaccination, people will be less protected, especially from the highly contagious Delta variant, which could increase breakthrough infections.

Booster doses are seen as a way to shore up immune protection against SARS-CoV-2, the coronavirus that causes COVID-19.

However, the booster shot debate is more complicated than this.

When talking about how well COVID-19 vaccines work over time, there’s not only one type of effectiveness. Some vaccines might still prevent most people from getting severely ill or dying but may have less protection against infection that leads to minor symptoms.

In addition, antibodies are only one tool used by the immune system to fight infection. Focusing solely on antibody levels misses the protection offered by the other parts of the immune system, some of it longer-lived.

Still, it’s important to understand how antibodies work and what waning levels might mean for protection against COVID-19.

Antibodies are Y-shaped proteins the immune system produces in response to an infection. They recognize and bind to specific molecular structures — known as antigens — such as those found on the surface of a virus or bacterium.

Many of the antibodies involved in preventing coronavirus infection bind to the virus’s spike protein on the surface, which the virus uses to infect cells.

Antibodies are produced by immune cells called B cells, found in the blood, lymph nodes, spleen, and other tissues. Each B cell produces a specific type of antibody.

Scientists estimate that the human immune system can produce at least a trillion unique antibodies, although it could be substantially higher.

When the body encounters a virus or other pathogen for the first time, and a B cell can bind to that pathogen, the B cell is activated.

Once activated, a B cell multiplies and forms different cells, including plasma cells, which are antibody-producing factories.

Antibodies remain in the body for some time after infection, although their numbers wane over months or years, depending on the pathogen and other factors.

B cells and antibodies are part of the adaptive immune system, the branch that targets specific pathogens.

The other branch is known as the innate immune system, which provides a general defense against infection.

These two branches can work together to fend off a virus or bacterium before you get severely ill. If there is a virus or bacterium that your immune system has never encountered before, the innate immune response may sense something is wrong and respond quickly to an invading virus or bacterium.

This is important because it can take days to weeks for the adaptive immune system to effectively build up enough antibodies to fight the specific pathogen.

However, once your immune system has that exposure to the pathogen, it can then be ready to respond more quickly next time. Meaning it may be able to fend off invading bacterium or virus you’re exposed to before you develop any symptoms.

“If you’ve been exposed for the first time to a particular pathogen, and your adaptive immune system was involved, you will develop what are called memory cells — both on the T-cell side and the B-cell side,” explained Ralph Pantophlet, PhD, an associate professor at Simon Fraser University who studies antibody responses to HIV and other viruses.

One type of T cell, called helper T cells, stimulates B cells to produce antibodies. Another type, known as killer T cells, attacks cells that have already been infected by a pathogen.

“If you are re-exposed to the same pathogen or a very similar one, it’s usually the antibodies that help protect or blunt that second exposure,” said Pantophlet.

Vaccines trigger a similar immune response without the risk of severe disease that comes with natural infection.

“[Vaccination] is basically a trick to provide the body with antibodies,” said Pantophlet, “so when you are exposed to ‘the real thing,’ you are protected, at least somewhat, from that assault.”

Vaccines accomplish this by presenting the immune system with an antigen from a pathogen.

Some vaccines contain the entire pathogen but in a weakened or inactivated form. Others contain only a specific piece of the pathogen.

The COVID-19 mRNA vaccines teach our cells how to make antibodies that target the coronavirus spike protein.

The immune system doesn’t produce only one antibody in response to a pathogen, but many different kinds. Some of these antibodies bind strongly to an antigen, others less so.

They can also be divided into neutralizing and non-neutralizing antibodies. As the name suggests, neutralizing antibodies can “neutralize” a pathogen.

For example, to respond to SARS-CoV-2, certain neutralizing antibodies bind tightly to the coronavirus spike protein and keep it from infecting the cell.

Although non-neutralizing antibodies don’t do this — or do it only weakly — they can still play a role in fighting pathogens.

“Non-neutralizing antibodies do not protect the cell from infection,” said Pantophlet. “However, non-neutralizing antibodies can recognize viral antigens that are exposed, or presented, on the surface of infected cells.”

When non-neutralizing antibodies bind to these surface antigens, other parts of the immune system can come along and eliminate the infected cells.

Pantophlet says that for COVID-19, most labs measure neutralizing antibodies “because that gives you a reasonable measure of protection [against infection].”

However, with COVID-19, he says we don’t yet have a clear sense of how high neutralizing antibody levels need to be to provide some protection from infection or severe disease.

Emily S. Barrett, PhD, an associate professor of biostatistics and epidemiology at the Rutgers School of Public Health, said identifying this minimum immune response is complicated because the immune system has other ways of protecting you besides antibodies. This includes the cellular, or T-cell-mediated, immune response.

“So, unfortunately, although we would all like to identify a threshold of protection, there’s no simple answer at the moment,” she said.

Still, “what we do know from just monitoring and measuring vaccine effectiveness,” said Pantophlet, “is that as the level of neutralizing antibodies decline, there is more chance of a breakthrough infection.”

In recent weeks, scientists have inched closer to defining this protective immune response — or “correlate of protection” — for COVID-19, but we’re not quite there yet.

In the meantime, scientists rely on other measures to know how well vaccines are working. This includes looking at the effectiveness of vaccines in the real world, both in certain groups of people and over time.

This is the approach that Israel used in deciding to roll out COVID-19 boosters over the summer.

Data from the country showed that breakthrough infections were occurring more often in people who were vaccinated earlier in the year than those vaccinated more recently.

The lack of a correlate of protection for COVID-19 is also why you can’t take an antibody test — after vaccination or natural infection — to see how well protected you are against the coronavirus.

After vaccination or natural infection, antibody levels increase but then start to decline. This is not unexpected.

“Antibodies only survive for a certain amount of time,” said Pantophlet, “and it depends on a whole bunch of biological factors as to how long they may persist.”

How long antibodies remain in the blood varies.

After two doses of the measles vaccine, antibody levels against the measles virus persist for at least 10 years, according to some research.

But with the COVID-19 mRNA vaccines, some studies have found that antibody levels start to drop within several weeks after the second dose.

This doesn’t immediately translate into a noticeable loss of immune protection.

However, research suggests that the effectiveness of the Pfizer-BioNTech and Oxford/AstraZeneca vaccines starts to wane around 6 months after the second dose.

“It’s clear that once [antibody levels] start to go down to a particular level, your likelihood of getting a breakthrough infection increases,” said Pantophlet. “Basically, all that means is that the virus has a greater chance of being able to infect you.”

But “that does not automatically translate to you ending up in a hospital or developing severe disease,” he added.

According to a recent Centers for Disease Control and Prevention (CDC) study, 2 to 12 weeks after the second dose of an mRNA vaccine, the vaccine effectiveness against hospitalization was 86 percent overall. After 13 to 24 weeks, it was 84 percent.

This decrease was not statistically significant.

Even several months after COVID-19 vaccination, “it appears that your immune system as a whole — antibodies, T cells and the other parts that are involved — have the ability to protect you enough that you don’t necessarily end up in the hospital,” said Pantophlet.

“But we don’t know — and this is this is a big ‘if’ — whether that protection will remain for another 6 months,” he said. “And that’s why there’s this debate as to whether a booster should be given.”

Scientists continue to monitor breakthrough infections and people’s immune responses to understand how long the immune protection lasts after COVID-19 vaccination or natural infection.

Because antibodies are proteins, they cannot replicate. In contrast, antibody-producing B cells can linger in the body and multiply when needed.

One study found that SARS-CoV-2 antibodies are still detectable after 11 months. Researchers also found plasma cells in the bone marrow capable of producing these antibodies if needed.

One of the study’s authors told NPR that these cells might be capable of producing antibodies for decades.

However, if the coronavirus changes significantly during that time, the immune system may need to learn to recognize and attack this new variant.

Understanding how well a certain antibody level protects against coronavirus infection or severe COVID-19 is also complicated by other factors that can affect the effectiveness of a vaccine.

A vaccine’s effectiveness means how well it works in the real world.

This is in contrast to its efficacy, which is a measure of how well a vaccine works in a clinical trial. During a vaccine trial, researchers try to consider other factors that can influence the risk of infection or severe disease.

Whether a vaccinated person wears a face mask or practices physical distancing can influence their risk of infection after vaccination. Even community-wide mask or vaccine mandates can influence vaccine effectiveness.

Shortly after California dropped its mask mandate in June of this year, coronavirus cases among fully vaccinated UC San Diego Health employees had risen compared to earlier in the year, according to a recent study.

This also coincided with the spread of the Delta variant, which may have also increased the risk of breakthrough infections.

Still, researchers found that people vaccinated in January and February had a higher risk of breakthrough infections than those vaccinated in March through May.

A combination of these factors is likely at work.

Although scientists often look at vaccine effectiveness for large groups, people’s immune response to vaccination and natural infection can vary, sometimes widely.

In one study, researchers found that people with severe symptoms of COVID-19 were more likely to have detectable antibody levels than those with mild/moderate symptoms. People with no symptoms had even lower antibody levels.

“This was a pattern that emerged almost immediately following infection and persisted throughout up to 6 months of follow-up,” said Barrett, one of the study’s authors.

Most study participants had sustained antibody levels up to 6 months after infection, but the levels increased differently during that time based on symptoms.

People with severe symptoms saw a sharp rise in antibody levels within the first 2 months, while people with asymptomatic infections had slow increases in antibody levels over 6 months.

Researchers did not look at whether people with higher levels of antibodies were better protected against reinfection.

However, “antibodies were detectable in the vast majority of infected individuals,” said Barrett, “and you don’t need high circulating antibody counts to mount a response to an infection.”

Another study found that even people who had mild COVID-19 cases appear to be protected against reinfection, at least during the 6 months after infection.

When it comes to waning antibody levels after vaccination, one preprint study suggests that different groups see a similar decline.

Researchers studied blood samples from 120 nursing home residents and 92 healthcare workers who had received 2 doses of the Pfizer-BioNTech COVID-19 vaccine.

After 6 months, antibody levels decreased more than 84 percent in both groups.

Researchers also found that the declines were similar in people who had previously contracted the coronavirus compared to those who were “infection-naive.”

However, older adults who were infection-naive generated less of an initial antibody response to vaccination.

This kind of lower immune response occurs among this age group with other vaccines, including the seasonal flu vaccine.

By 6 months after vaccination, 70 percent of these nursing home residents had “neutralizing [antibody] levels that were very low, at the limit of detection,” said study author Dr. David Canaday, a professor in the School of Medicine at Case Western University.

The study has not yet been peer-reviewed.

Canaday said the waning antibody levels, coupled with the lower starting point for nursing home residents, are particularly concerning for this group because they may be frail or have other chronic health conditions.

“This huge drop in antibodies puts them at continued high risk, and even higher risk, due to those extra conditions,” he said. “This means a higher risk of requiring hospitalization or of passing away.”

People with weakened immune systems may also not generate a strong immune response to vaccination, putting them at a lower starting point for antibody levels.

This includes organ transplant recipients and people undergoing cancer treatment or taking drugs that suppress the immune system.

In the CDC study, the vaccine effectiveness against hospitalization in people with immunocompromising conditions was 63 percent over the entire study period.

This is why the CDC recommends that certain immunocompromised people who are fully vaccinated with an mRNA COVID-19 vaccine receive an additional dose.

This is not considered a booster, which is given in response to waning antibody levels. Instead, the additional dose is meant to help immunocompromised people reach a starting level more on par with the rest of the population.

The CDC is waiting for more data before recommending a second Johnson and Johnson vaccine dose for people with weakened immune systems.

While conversations around the COVID-19 vaccines have shifted to potentially waning immunity and the need for boosters, Barrett said people should keep the big picture in mind.

“The most important thing for the public to know is that all of the [COVID-19] vaccines currently being used generate a robust antibody response,” she said. “That is absolutely the best way to protect yourself against infection.”